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Effect of temperature, age and lifespan extending interventions on Caenorhabditis elegans models of amyloid beta pathology

Kelkar, Rachana S. and Wipf, Peter and Ghazi, Arjumand (2019) Effect of temperature, age and lifespan extending interventions on Caenorhabditis elegans models of amyloid beta pathology. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that accounts for 60-70% of all dementia cases worldwide. The hallmark of AD is neuronal death precipitated by accrual of intercellular amyloid (Aβ) aggregates and intracellular neurofibrillary (NFT) Tau tangles. AD risk factors include age, genetics and environment. Despite intense research, the genetic and biochemical underpinnings of AD are poorly understood, and no drugs have been discovered for curing the disease. In this project, we aimed to study the impact of temperature, age and longevity-promoting interventions on two Caenorhabditis elegans transgenic strains modeling aspects of Aβ pathophysiology, by expressing full length human (1-42 amino acids) Aβ peptide in muscles or neurons. Since AD is an age-related disease, we first examined how age influenced the dynamics of Aβ-mediated phenotypes, followed by the impact of an additional stress modality- high temperature. As previously reported, worms expressing Aβ in muscles exhibited full body paralysis and mobility defects at high temperatures of 25 °C. Contrarily, the animals expressing Aβ in neurons did not show any paralysis but underwent distinct mobility defects under temperature stress. Surprisingly, we discovered that in both models the extent of pathology was only moderately aggravated by increasing age alone, or upon combining age and temperature stressors. Since aging is the biggest risk factor for AD, we also asked if genetic or chemical interventions known to increase lifespan could impact the phenotypes of the worm Aβ models. We found that a known lifespan-extending drug, promethazine•HCl, significantly delayed the onset of paralysis and mobility defects in the Aβ (muscle) model on day 1 of the animal. Similarly, we found that two known lifespan extending transcription factors, DAF-16 and NHR-49, also played an important role in alleviating Aβ phenotypes on day 1 and influenced the ability of promethazine•HCl to retard Aβ pathology. Overall, in characterizing an in vivo worm platform for identifying drugs and genes that impact AD, we have delineated the interlinked effects of age, temperature and genetic environment on Aβ pathology.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kelkar, Rachana S.rsk43@pitt.eduRSK43
Wipf, Peterpwipf@pitt.eduPWIPF
Ghazi, Arjumandghazia@pitt.eduGHAZIA
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWipf, Peterpwipf@pitt.eduPWIPF
Committee CoChairGhazi, Arjumandghazia@pitt.eduGHAZIA
Committee MemberGold, Barrygoldbi@pitt.eduGOLDBI
Date: 15 April 2019
Date Type: Publication
Defense Date: 29 March 2019
Approval Date: 15 April 2019
Submission Date: 12 April 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 73
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Alzheimer’s disease, C. elegans, animal model, promethazine, lifespan extending drug, genetics, daf-16, nhr-49, glp-1
Date Deposited: 15 Apr 2019 18:35
Last Modified: 15 Apr 2019 18:35
URI: http://d-scholarship.pitt.edu/id/eprint/36478

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